ArticlePDF AvailableLiterature Review

Pain level between clear aligners and fixed appliances: a systematic review

December 2020
Progress in Orthodontics 21(1):3

DOI:10.1186/s40510-019-0303-z

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Authors:

Paula Coutinho Cardoso

Federal University of Pará

Daybelis Gonzalez Espinosa

Catholic University Redemptoris Mater

Paulo Mecenas

Federal University of Pará

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Objectives: To assess if there is any difference in pain levels between orthodontic treatment with clear aligners or fixed appliances. Materials and methods: An electronic search was completed in PubMed, The Cochrane Database, Web of Science, Scopus, Lilacs, Google Scholar, Clinical Trials, and OpenGrey databases without any restrictions until February 2019. All comparative study types contrasting pain levels between clear aligners and fixed appliances were included. The risk of bias (RoB) was assessed using the Newcastle-Ottawa Scale, ROBINS-I-Tool, or ROB 2.0 according to the study design. The level of evidence was assessed through the GRADE tool. Results: After removal of duplicates, exclusion by title and abstract, and reading the full text, only seven articles were included. Five were prospective non-randomized clinical trials (CCT), one was a cross-sectional study, and one was a randomized clinical trial (RCT). Two studies presented a high RoB, three a moderate RoB, and two a low RoB (including the RCT). A meta-analysis was not performed because of clinical, statistical, and methodological heterogeneity. Most of the studies found that pain levels in patients treated with Invisalign were lower than those treated with conventional fixed appliances during the first days of treatment. Differences disappeared thereafter. No evidence was identified for other brands of clear aligners. Conclusions: Based on a moderate level of certainty, orthodontic patients treated with Invisalign appear to feel lower levels of pain than those treated with fixed appliances during the first few days of treatment. Thereafter (up to 3 months), differences were not noted. Malocclusion complexity level among included studies was mild. Pain is one of many considerations and predictability and technical outcome are more important, mainly considering that the difference does not seem to occur after the first months of the orthodontic treatment.

Diagram with number of records at each stage of the review according to PRISMA statement

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Extraction of data

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Risk of bias of included studies

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Risk of bias of the included studies, according to the ROBINS-I tool

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R E V I E W Open Access

Pain level between clear aligners and fixed

appliances: a systematic review

Paula Coutinho Cardoso

, Daybelis Gonzalez Espinosa

, Paulo Mecenas

, Carlos Flores-Mir

and

David Normando

Abstract

Objectives: To assess if there is any difference in pain levels between orthodontic treatment with clear aligners or

fixed appliances.

Materials and methods: An electronic search was completed in PubMed, The Cochrane Database, Web of Science,

Scopus, Lilacs, Google Scholar, Clinical Trials, and OpenGrey databases without any restrictions until February 2019.

All comparative study types contrasting pain levels between clear aligners and fixed appliances were included. The

risk of bias (RoB) was assessed using the Newcastle-Ottawa Scale, ROBINS-I-Tool, or ROB 2.0 according to the study

design. The level of evidence was assessed through the GRADE tool.

Results: After removal of duplicates, exclusion by title and abstract, and reading the full text, only seven articles

were included. Five were prospective non-randomized clinical trials (CCT), one was a cross-sectional study, and one

was a randomized clinical trial (RCT). Two studies presented a high RoB, three a moderate RoB, and two a low RoB

(including the RCT). A meta-analysis was not performed because of clinical, statistical, and methodological

heterogeneity. Most of the studies found that pain levels in patients treated with Invisalign were lower than

those treated with conventional fixed appliances during the first days of treatment. Differences disappeared

thereafter. No evidence was identified for other brands of clear aligners.

Conclusions: Based on a moderate level of certainty, orthodontic patients treated with Invisalign appear to feel lower

levels of pain than those treated with fixed appliances during the first few days of treatment. Thereafter (up to 3 months),

differences were not noted. Malocclusion complexity level among included studies was mild. Pain is one of many

considerations and predictability and technical outcome are more important, mainly considering that the difference does

not seem to occur after the first months of the orthodontic treatment.

Keywords: Orthodontic appliances, Pain, Invisalign, Malocclusion

Introduction

Pain is a subjective response and presents a large number

of individual variations under the same trigger conditions.

It depends on several factors such as age, sex, individual

pain threshold, emotional state, stress, amount of applied

force, cultural differences, and previous experiences of

pain [1,2]. Pain complaints are a common feature during

orthodontic treatment [3] directly influencing patient’s

satisfaction [4]. It is one of the main reasons for orthodon-

tic treatment discontinuation [5].

It is well known that during orthodontic treatment

with fixed appliances, it is common to feel pain and dis-

comfort [6], reaching its peak 24 h after arch insertion,

and being almost imperceptible 7 days after [7,8]. How-

ever, the type of the appliances may have an influence

on the pain and discomfort reported by the patients due

to the type of force applied. Removable appliances pro-

duce intermittent forces, which allow the tissues to re-

organize before compressive forces are reapplied [9].

Regarding studies that have evaluated pain levels with

clear aligners compared to fixed appliances, some studies

have found positive [2,10,11] or negativ e[12] results

related to clear aligners.

International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and

reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to

the Creative Commons license, and indicate if changes were made.

* Correspondence: davidnormando@hotmail.com

Faculty of Dentistry, Federal University of Pará (UFPA), Rua Augusto Correa

01, Belém, Pará 66075-110, Brazil

Full list of author information is available at the end of the article

Cardoso et al. Progress in Orthodontics (2020) 21:3

https://doi.org/10.1186/s40510-019-0303-z

When comparing quality of life (QoL) between pa-

tients treated with fixed appliances and Invisalign (Align

Technology, San Jose, CA), it was observed that both

presented similar QoL results, except under the category

of eating and chewing where the aligner group showed

better results [13].

Systematic reviews have evaluated the efficiency of

orthodontic treatment with clear aligners and they sug-

gested that the outcomes are not as accurate as those

with fixed appliances [14–16]. On the other hand, treat-

ment done with clear aligners present some advantages

such as overall decreased treatment and chair time in

patients with mild to moderate malocclusions [17]. Be-

sides that, studies have shown that gingival health tends

to be better, based on the periodontal health index, in

patients treated with clear aligners [18,19].

There are controversial findings regarding pain level

during orthodontic treatment with fixed appliances ver-

sus clear aligners. Thus, the aim of this systematic re-

view was to evaluate the level of pain during orthodontic

treatment in patients treated with clear aligners com-

pared with patients treated with fixed appliances.

Material and methods

Protocol and registration

The present systematic review was registered in the

PROSPERO database (http://www.crd.york.ac.uk/PROS-

PERO, PROTOCOL: CRD42019131359) and was done ac-

cording to the Preferred Reporting Items for Systematic

Review and Meta-Analysis (PRISMA) guidelines (www.

prisma-statment.org).

Eligibility criteria

The following criteria were used in the selection of the

articles:

1. Study design: Randomized or non-randomized con-

trolled clinical trials and cross-sectional studies.

2. Population: Adult patients during orthodontic

treatment.

3. Intervention: Patients treated with clear aligners.

4. Comparison: Patients treated with conventional

fixed appliances.

5. Outcome: Pain level.

6. Exclusion criteria: Laboratory studies, clinical trials,

case reports, literature reviews, and studies done

with patients with syndromes and/or craniofacial

deformities were excluded from the research.

Information sources, search strategy, and study selection

There were no restrictions on languages and dates of

publication. The search was completed by two authors

(P.C.C and D.G.E.) until February 2019. The search was

performed in the following databases: Cochrane,

PubMed, Scopus, Google Scholar, Lilacs, Web of Sci-

ence, Clinical Trials, and OpenGrey. Specific search

strategies per database are shown in Appendix 1. A hand

search was also performed.

The included articles were exported to a bibliography

reference manager (Mendeley, version 1.19.4 Elsevier).

In case of disagreement, a third evaluator (D.N) opinion

was consulted.

Data items and collection

The data collection in duplicate was carried out accord-

ing to the following criteria: type of study, sample size,

intervention, assessment of pain, time of evaluation, se-

quence of the archwires and aligners, pain outcomes,

overall outcomes, analgesic consumption and author’s

conclusion (Table 1).

RoB/quality assessment in individual studies

For the cross-sectional study, the Newcastle-Ottawa

Scale adapted to cross-sectional studies was used [21].

The evaluation was done by counting stars acquired in

each category (Table 2).

For the evaluation of RoB for the non-randomized clin-

ical trials, the ROBINS-I-tool [22] was used. The evaluated

criteria were divided into pre-intervention, intervention,

and post-intervention categories. The RoB was individu-

ally analyzed for each study and classified as low, moder-

ate, serious, critical, and no information (Table 3).

For the randomized clinical trial, the RoB was per-

formed using Cochrane Collaboration RoB 2.0 tool [23],

analyzing six domains: random sequence generation, allo-

cation concealment, blinding of patients and personnel,

blinding of outcome assessor, incomplete outcome data,

and selective outcome reporting (Table 4).

Summary measures

Clinical heterogeneity was measured assessing the treat-

ment protocol, according to the archwire sequences and

use of the aligners, times of evaluation of pain levels, use

of analgesics during orthodontic treatment, different

prescriptions of the fixed appliances, and other out-

comes such as soft tissue irritation and eating disorders.

The assessment of pain levels was evaluated through a

visual analog scale (VAS).

For continuous outcomes, descriptive statistics, such

as mean differences and standard deviations, were used

to summarize the data from the included studies.

RoB/quality assessment among studies

The quality of evidence of the included studies was

made according to The Grading of Recommendations

Assessment, Development and Evaluation (GRADEpro

Cardoso et al. Progress in Orthodontics (2020) 21:3 Page 2 of 17

Table 1 Extraction of data

Authors,

(year)

Type of

study

(country)

Sample

size, male/female

ratio, and age

(mean ± sd) per

group (age)

Intervention Assessment of

pain

Time of

evaluation

Sequence Pain

outcomes

Overall

outcomes

Other

outcomes

Analgesic consumption Author’s

conclusion

Archwire Align

Almasoud

(2018) [10]

Prospective

CCT (Saudi

Arabia)

CG: n= 32, 12M/

20F (23.56 years

± 5.44)

IG: n= 32p,

10M/22F (28.47

years ± 8.17)

CG: Passive

self-ligating

(Damon)

IG: Invisalign

VAS 10 cm 4 h; 24 h;

3rd, and 7th

day

.014″

NiTi

Firsts

aligners

Patients

treated with

IG had

significantly

lower pain

level than

did those in

CG at all

timepoints.

The highest

pain level

was 24 h

Higher

numbers of

participants

reported

having pain

at 4 h and

lower

number in

day 7

patients in

CG took

analgesics

when

compared

with the IG

Yes (acetaminophen/

paracetamol)

Patients

treated with

Invisalign

observed lower

pain than did

with braces.

↑of pain was

experienced at

24 h and ↓at

day 7 in both

groups

Flores-mir

et al.

(2018) [13]

Cross-

sectional

(Alberta,

Canada)

CG: n=4,NA

(NA)

IG: n= 81, NA

(NA)

CG:

conventional

fixed

appliance)

IG: Invisalign

DIDL (Dental

Impacts on

Daily Living)

PSQ (Patient

Satisfaction

Questionnaire)

End of

treatment

NA NA Similar

satisfaction

Eating and

chewing: IG

reported a

better

satisfaction

Patient

satisfaction

remained

relatively

similar 6

months

later for the

bracket-type

treatment

No Both groups

treated

patients had

statistically

similar

satisfaction

outcomes,

except for

eating and

chewing

Fujiyama

et al.

(2014) [20]

Prospective

CCT (Ohio)

CG: n= 55, 25M/

35F (26.45 years

± 5.45)

:n= 38, 10M/

28F (26.64 years

± 5.69)

:n= 52, 19M/

33F (25.24 years

± 6.51)

CG: Edgewise

(straight wire

with .018

slot)

: Invisalign

(IG)

: Edgewise

+ Invisalign

(EIG)

VAS 10 cm 1°: 60 s, 6 h,

12 h, 1–7

days

2°: 3 weeks

after

3°: 5 weeks

after

Slot

.018″

Use 20

h/day

EG was

significantly

higher than

others

IG was

significantly

↑than

others

(intensity of

pain, no. of

days,

discomfort)

NA No Invisalign

causes less

pain compared

to the

traditional

edgewise

treatment;

problems such

as tray

deformation

must be

carefully

checked in the

use of

Invisalign.

Mais-

Damois

et al.

(2015)

Prospective

CCT

(Canada)

:n= 19, NA

(NA)

:n= 20, NA

(NA) 18M/21F

(14.5 years)

IG: n= 31, 11M/

20F (16 years)

: Damon

: Speed

IG: Invisalign

VAS 0 h, 5 h, 24

h, 3rd, 7th,

14th day

-.016″NiTi

-.016″CuNiTi

-.016″× .022″

CuNiTi

-.019″× .025″

CuNiTi

Aligners 1,

4, 7, and 10

Invisalign

group

reported

lower pain

than fixed

appliances

Patients

with

Invisalign

reported

significantly

less tissue

irritation

than

Quality of life

was slightly

affected in

the first phase

higher in CG

than in IG)

Yes

Exclusively

during the

first week

treatment

Perception of

pain with

Invisalign was

lower than

with fixed

appliance. This

method of

treatment is an

Changed each 2 weeks

Cardoso et al. Progress in Orthodontics (2020) 21:3 Page 3 of 17

Table 1 Extraction of data (Continued)

Authors,

(year)

Type of

study

(country)

Sample

size, male/female

ratio, and age

(mean ± sd) per

group (age)

Intervention Assessment of

pain

Time of

evaluation

Sequence Pain

outcomes

Overall

outcomes

Other

outcomes

Analgesic consumption Author’s

conclusion

Archwire Align

patients

with fixed

brackets

attractive

therapy for

patients

wishing for an

esthetic

treatment.

Miller

et al.

(2007) [11]

Prospective

CCT (USA)

CG: n= 27, 6M/

21F (28.6 years ±

8.7)

IG: n= 33, 11M/

22F (38 years ±

12.4)

CG:

preadjusted

fixed

appliance

(NA)

IG: Invisalign

- Daily diary:

functional,

psychosocial

and pain-

(Likert Scale)

- Pain (VAS)

NA NA NA Fixed

appliances

group

reported

more pain

beginning

at day 1

through day

Invisalign

and fixed

appliances

reported

decreases in

OHRQL after

treatment

beginning

The fixed

appliances

subjects took

more pain

medication

during days 2

and 3

Yes The Invisalign

subjects’

overall OHRQL

was better

than that of

the fixed

appliances

subjects.

Shalish

et al.

(2011) [12]

Prospective

CCT (Israel)

:n= 28,

14M/14F (NA)

:n= 19, 4M/

15F (NA)

IG: n= 21, 5M/

16 F (NA)

: Buccal

group

(straight wire

GAC and

Ormco)

: Lingual

group

(Incognito)

IG: Invisalign

group

HRQoL

VAS (pain)

consecutive

days and at

day 14

.014″NiTi NA Pain levels

decreased

from the 1

to 7 day. ↑

Invisalign

and Lingual

group

Day 1: ↑%

pain in

Invisalign

group;

Day 2:

Lingual

group;

Small % of

buccal

group

reported

severe pain

Oral

dysfunction,

disturbances

in eating,

general

activity,

recovery time:

↑Lingual

group

Yes

Highest in

the

Lingual

group

(similar to

the buccal

group)

Lingual

appliance was

associated with

more severe

pain and

analgesic

consumption,

the ↑oral and

general

dysfunction,

and the most

difficult and

longest

recovery

White

et al.

(2017) [2]

RCT (USA) CG: n= 18, 6M/

12F (NA)

IG: n= 23, 11M/

12F (NA)

CG: Fixed

clear

appliance

upper arch

(Radiance)

and metal

brackets

lower arch

(Alexander)

IG: Invisalign

VAS (10 cm) Initial

adjustment:

daily diary

for 7

consecutive

days

Subsequent

adjustments

(2):

Daily diary

for 4 days

-.016″CuNiTi

-.017″× . 025″

CuNiTi

-.016″× .022″SS

-.017″× .025″SS

Change

each 2 week

and use 22

h/day

1°: higher in

CG;

2° 3°: higher

in CG

Discomfort

was

significantly

higher in

CG during

the 1st

week and

subsequent

adjustments

First 3 days

after

bonding:

discomfort

when

chewing

Analgesic

consumption:

higher in CG

in the first

week; 1° and

2° adjustment

no ≠

No ≠in sleep

disturbances

Yes Traditional

fixed

appliances

produced

significantly

discomfort

than did

aligners.

Patients

treated with

aligners and

fixed

appliances

reported

significantly

Cardoso et al. Progress in Orthodontics (2020) 21:3 Page 4 of 17

Table 1 Extraction of data (Continued)

Authors,

(year)

Type of

study

(country)

Sample

size, male/female

ratio, and age

(mean ± sd) per

group (age)

Intervention Assessment of

pain

Time of

evaluation

Sequence Pain

outcomes

Overall

outcomes

Other

outcomes

Analgesic consumption Author’s

conclusion

Archwire Align

with fixed

appliances.

less discomfort

at subsequent

adjustments

than after the

initial bonding

or appliance

delivery.

CCT non-randomized controlled clinical trial, RCT randomized clinical trial, VAS visual analog scale, OHRQL oral health-related quality of life, NA not available

Cardoso et al. Progress in Orthodontics (2020) 21:3 Page 5 of 17

Guideline Development Tool, available online at grade-

pro.org)[24].

Table 2 Risk of bias of the studies, according to the Newcastle-Ottawa Scale adapted for cross-sectional studies

Selection (maximum 5 stars) Comparability (maximum 2 stars) Outcome (maximum 5 stars) Total score (maximum 10)

Flores-Mir et al. 2018 [13]4 1 3 8

Newcastle-Ottawa Quality Assessment Scale (adapted for cross sectional studies)

Selection (maximum 5 stars):

1. Representativeness of the sample:

a)Truly representative of the average in the target population. * (all subjects or random sampling)

b)Somewhat representative of the average in the target population. * (nonrandom sampling)

c)Selected group of users.

d)No description of the sampling strategy.

2. Sample size:

a) Justified and satisfactory. *

b) Not justified.

3. Non-respondents:

a) Comparability between respondents and non-respondents characteristics is established, and the response rate is satisfactory. *

b) The response rate is unsatisfactory, or the comparability between respondents and non-respondents is unsatisfactory.

c) No description of the response rate or the characteristics of the responders and the non-responders.

4. Ascertainment of the exposure (risk factor):

a) Validated measurement tool. **

b) Non-validated measurement tool, but the tool is available or described.*

c) No description of the measurement tool.

Comparability (maximum 2 stars):

1. The subjects in different outcome groups are comparable, based on the study design or analysis. Confounding factors are controlled.

a) The study controls for the most important factor (select one). *

b) The study control for any additional factor. *

Outcome (maximum 3 stars):

1. Assessment of the outcome:

a) Independent blind assessment. **

b) Record linkage. **

c) Self-report. *

d) No description.

2. Statistical test:

a) The statistical test used to analyze the data is clearly described and appropriate, and the measurement of the association is presented, including confidence

intervals and the probability level (pvalue). *

b) The statistical test is not appropriate, not described or incomplete

Table 3 Risk of bias of included articles

Domain bias Description

Pre-intervention

Bias due to confounding Assessment of baseline in of certain number of participants by age and malocclusion description

Assessment of the method of pain evaluation

Assessment of time of evaluation

Bias in selection of participants into

the study

Assessment of participants eligibility criteria

Evaluation of eligible participants exclusion or difference between the follow-up period

Intervention

Bias in classification of interventions Assessment of the intervention status—use of the aligner was not properly described (change of the

aligner)

Use of additional orthodontic methods to correct malocclusion (ex: MI, elastic)

Use of analgesic

Post-intervention

Bias due to deviations from intended

interventions

Evaluation of the systematic differences between the intervention (group that used the aligner) and the

comparison group when there is no information about the evaluation of the pain

Use of analgesic for pain relief during orthodontic treatment

Bias due to missing data In the event of loss of follow-up, incomplete collection of data and exclusion of participants from the

analysis

Bias in measurement of the outcomes When assessments of pain perception were not reported or were measured with error

When not all the measures established in the different treatment times are presented

When the use of analgesic is mentioned or not

Bias in selection of the reported

results

Selective report of results when the effect of all measurements of results has not been fully reported

Cardoso et al. Progress in Orthodontics (2020) 21:3 Page 6 of 17

Synthesis of results

A meta-analysis was not justifiable because of the large

amount of clinical, statistical, and methodological

heterogeneity.

Results

Study selection and characteristics

A total of 1773 studies were identified in the following

databases: PubMed (663), Cochrane (124), Web of Sci-

ence (68), Scopus (13), Lilacs (2), Google Scholar (895)

Clinical Trials (5), and OpenGrey (3). A manual search

was also undertaken but no articles were found. The

identified articles were exported to the Mendeley Desk-

top (version 1.19.4) reference manager to remove dupli-

cates, and a total of 1625 articles remained after the

duplicates were removed. A flow diagram of the process

of identification, inclusion, and exclusion of studies is

presented in Fig. 1.

The exclusion of articles by title and abstract was done

by two evaluators (PC and DG), and in the end, 29 stud-

ies were selected to be evaluated by full text. Of these,

22 were excluded because 2 were a literature review, 14

did not have a control or an intervention group, 3 failed

to evaluate pain, and 3 were not related to the objectives

of this systematic review (Table 5).

A total of seven studies were finally included. Five

were prospective non-randomized clinical studies [10–

12,20,25], one was a cross-sectional study [13], and one

was a randomized clinical trial [2]. The mean age of the

control group (group with fixed appliances) ranged be-

tween 23.56 [10] and 28.6 [11], but four studies [2,12,

13,25] did not report this information. A homogeneity

was observed due the type of aligner used in all studies

(Invisalign aligner); however, different types of fixed ap-

pliances were used as a control group, such as Edgewise

[20], Damon Q (Ormco, Orange, CA) [10,25] (Ormco,

Glendora, CA), Speed [25] (Strite Industries Ltd., On-

tario, Canada), Radiance (American Orthodontics, She-

boygan, WI) in the maxillary arch, and Alexander

(American Orthodontics, Sheboygan, WI) in the man-

dibular arch [2]. One study just reported a use of a

straight-wire appliance from GAC or Ormco [12], and

two studies did not report any information [11,13].

In five studies [2,10,20,25,26], a VAS was used as a

method for evaluating pain level, one study used a ques-

tionnaire at the end of treatment [13], and two studies

used both methods [11,12].

When evaluating follow-up time, six studies [2,10–12,

20,25] reported daily evaluations during 1 week until 3

months of follow-up, and only one study evaluated pain

level at the end of treatment [13].

RoB within studies

The Newcastle-Ottawa scale for cross-sectional studies

was applied for one study [13] and was classified with a

good quality of evidence. A lower grade was applied for

the selection domain due to the representativeness of

the sample that was ranked as selected groups of users.

The ROBINS-I-Tool (Risk of Bias in Non-randomized

Studies-of Interventions) was used in five studies [10–

12,20,25] (Table 1). Reasons related to increased RoB

included confusing information (description of the mal-

occlusion, method of pain evaluation, and follow-up

time). Only one [10] study presented a low RoB and four

[11,12,20,25] showed a moderate RoB (Table 6). The

major reason for this grading was related to the use of

analgesics and this information was not properly re-

ported (use or not). One study [11] was classified as high

RoB in the intervention domain due to bias in classifica-

tion of interventions, which included the assessment of

the intervention status, use of additional orthodontic

methods to correct, and use of analgesic.

For the randomized clinical trial [2], RoB was evalu-

ated according to the Cochrane Collaboration RoB 2.0

tool, which presented a low RoB in all domains: random

sequence generation, allocation concealment, blinding of

patients and personnel, blinding of outcome assessor, in-

complete outcome data, and selective outcome reporting

(Table 3).

Summary of individual studies’results

Among all included studies [2,10–13,20,25], pain

scores were obtained 24 h after the beginning of treat-

ment, and four included articles reported higher pain

levels for fixed appliances during this period. However,

only one investigation [10] found a statistically signifi-

cant difference. Two others studies [2,11] only reported

a significant difference on day 3 and on day 4. Both

studies reported that pain levels were higher in the

group treated with fixed appliances. During days 5–7,

only one study [2] observed a significantly higher level of

pain in the patients with fixed appliances, but the high-

est level of pain was on the third day. Two studies [12,

25] evaluated pain on day 14 and reported no significant

Table 4 Risk of bias of included studies

Risk of bias

Study Random sequence

generation

Allocation

concealment

Blinding of patients,

personnel

Blinding of outcome

assessor

Incomplete

outcome data

Selective outcome

reporting

White et al. (2017) [2] Low Low Low Low Low Low

Cardoso et al. Progress in Orthodontics (2020) 21:3 Page 7 of 17

differences (p> 0.05) in pain level between groups. Only

one study [2] performed this evaluation 2 months after

starting treatment, and significant differences were

found only on day 1 (p= 0.045) and day 2 (p= 0.041),

with higher levels of pain in the control groups.

One study [25] compared different prescriptions of

self-ligating appliances, Speed vs Damon, with Invisa-

lign. Statistical differences were found between the

Speed and Invisalign prescription only in the first ac-

tivation, .016″NiTi versus first aligner, and in the

fourth phase, .019″× .025″CuNiTi and tenth

aligner, 3 days after a follow-up appliance. In these

twoevaluations,thegroupthatusedafixedappliance

presented higher levels of pain when compared to the

Invisalign group. Although one paper [12]reporteda

higher pain level for the aligner group for all

Fig. 1 Diagram with number of records at each stage of the review according to PRISMA statement

Cardoso et al. Progress in Orthodontics (2020) 21:3 Page 8 of 17

evaluation times, 24 h and 14 days, no statistically signifi-

cant (p> 0.05) difference was found for any time point.

Five studies [2,10–12,25] reported the use of analge-

sics, of which three studies found statistical differences

in time points for 4 h [10](p= 0.001), 24 h [10,25](p=

0.001 and p= 0.025), day 2 [2,25](p= 0.0023 and p<

0.05), and day 3 [11](p= 0.006), and in all these cases,

patients treated with fixed appliances reported a higher

analgesic consumption. Only one study [12] observed

that analgesic use was higher in the Invisalign group,

since they discontinued their use on day 6, which was

different from the control group that stopped their use on

day 4. One study [13] also assessed QoL and patient satis-

faction during orthodontic treatment, finding a statistical

difference only in the evaluation of eating and chewing,

where the Invisalign group presented a better response

than the control group (47% and 24%, respectively).

Soft tissue irritation was reported to be lower in the

Invisalign group in two studies [12,25] as well as the as-

sessments related to eating disorders [12].

Certainty level

The quality of the articles was assessed using the GRADE

system described in Table 7. All timepoints evaluated in the

studies were rated with low certainty of evidence in all CCT

studies [10–12,20,25], except for the RCT [2]thatwas

rated with high certainty of evidence. Just one study [13]

was not included in the evaluation because it was a cross-

sectional study and had not made timepoint evaluations.

Synthesis of results and additional analyses

It was not possible to perform a meta-analysis because of

large amount of clinical, methodological, and statistical

Table 5 List of excluded studies (with reason)

Reference Reason for exclusion

Abu Alhaija et al. (2015) No intervention group

Ashkenazi et al. (2014) No intervention group

Bergius et al. (2000) Literature review

Bretz et al. (2018) No intervention group

Caniklioglu et al. (2004) No intervention group

Djeu et al (2014) No pain evaluation

Fetouh (2008) No pain evaluation

Fleming et al. (2009) No intervention group

Kavaliauskiene et al. (2012) No intervention group

Ke et al. (2019) No pain evaluation

Kim (2013) No control group

Mai-Tam (2018) Literature review

Maldotti et al. (2013) No control group

Noll et al. (2017) Study not related with the SR objective

Pacheco-Pereira et al. (2015) Study not related with the SR objective

Phuong (2018) Study not related with the SR objective

Polat (2007) No intervention group

Rakhshan (2015) No intervention group

Salcedo-Bugarín (2018) No intervention group

Scheurer et al. (1996) No intervention group

Sergl et al. (1998) No intervention group

Zealaiy et al. (2018) No intervention group

SR systematic review

Table 6 Risk of bias of the included studies, according to the ROBINS-I tool

Domains

Pre-intervention Intervention Post-intervention

Author Bias due to

confounding

Bias in selection of

participants for the

study

Bias in

classifying

interventions

Bias due to deviations

from intended

interventions

Bias due to

missing

data

Bias to

measuring

outcomes

Bias in

selecting

reported

results

Overall risk

of bias

judgment

Almasoud

(2018)

Low Low Low Moderate Low Low Low Moderate

Fujiyama

et al.

(2014)

Moderate Low Moderate Low Low Low Moderate Moderate

Mais-

Damois

et al.

(2015)

Moderate Low Low Moderate Low Low Moderate Moderate

Miller et al.

(2007)

Moderate High High Moderate Low Low Low High

Shalish

et al.

(2007)

Moderate Moderate Moderate Moderate Low Low Low Moderate

Cardoso et al. Progress in Orthodontics (2020) 21:3 Page 9 of 17

Table 7 Grading system according to GRADEpro

Clear aligners compared to fixed appliances for pain

Certainty assessment Summary of findings

No. of participants

(studies) followed

Risk of

bias

Inconsistency Indirectness Imprecision Publication bias Overall

certainty

evidence

Study event rates (%) Relative

effect

(95% CI)

Anticipated absolute effects

With fixed

appliances

With clear

aligners

Risk with

fixed

appliances

Risk difference

with clear

aligners

1st, 3rd, and 7th day (follow up: mean 1 days; assessed with VAS scale)

336 (5 non-

randomized

studies)

Serious

Not serious Very

serious

All plausible residual confounding would reduce the

demonstrated effect dose response gradient

⨁⨁◯◯

low

181

participants

155

participants

Not

estimable

Low

0 per 1.000

2nd, 4th, 5th, and 6th day (follow up: mean 1 days; assessed with VAS score)

234 (3 non-

randomized

studies)

Serious

Not serious Very

serious

All plausible residual confounding would reduce the

demonstrated effect dose response gradient

⨁⨁◯◯

low

110

participants

124

participants

Not

estimable

Low

0 per 1.000

14th day (follow up: mean 1 days; assessed with VAS score)

119 (2 non-

randomized

studies)

Serious

Not serious Very

serious

All plausible residual confounding would reduce the

demonstrated effect dose response gradient

⨁⨁◯◯

low

participants

Not

estimable

Low

0 per 1.000

21st, 22nd, 23rd, 36th, and 37th day (follow up: mean 1 days; assessed with VAS score)

93 (1 non-

randomized

study)

Not

serious

Very serious

Not serious Very

serious

All plausible residual confounding would reduce the

demonstrated effect dose response gradient

⨁⨁◯◯

low

participants

Not

estimable

Low

0 per 1.000

24th, 25th, 26th, 27th, 35th, 38th, 39th 40th, and 41st day (follow up: mean 1 days; assessed with VAS score)

93 (1 non-

randomized

study)

Not

serious

Very serious

Not serious Very

serious

All plausible residual confounding would reduce the

demonstrated effect dose response gradient

⨁⨁◯◯

low

participants

Not

estimable

Low

0 per 1.000

Baseline (follow up: mean 1 days; assessed with VAS SCORE)

223 (3 non-

randomized

studies)

Serious

a,c

Not serious Very

serious

All plausible residual confounding would reduce the

demonstrated effect dose response gradient

⨁⨁◯◯

low

121

participants

102

participants

Not

estimable

Low

0 per 1.000

Baseline, 1st, 2nd, 14th, 30th, 33rd, 34th, 60th, 61st, 62nd, 63rd, and 64th day (follow up: mean 1 days; assessed with VAS score)

41 (1 RCT) Not

serious

Not serious Not serious Very

serious

All plausible residual confounding would reduce the

demonstrated effect dose response gradient

⨁⨁⨁⨁

high

participants

Not

estimable

Low

0 per 1.000

3rd, 4th, 5th, 6th, 7th, 31st, and 32nd day (follow up: mean 1 days; assessed with VAS score)

41 (1 RCT) Not

serious

Not serious Not serious Very

serious

All plausible residual confounding would reduce the

demonstrated effect dose response gradient

⨁⨁⨁⨁

high

participants

Not

estimable

Low

0 per 1.000

CI confidence interval

This will down grade because one article was classified with a serious RoB

This will downgrade because the use of analgesic was not properly described and it may mask the real pain reported by the patients

This will downgrade because two articles were classified with moderate RoB

This will downgrade because one article as classified with a moderate RoB

Cardoso et al. Progress in Orthodontics (2020) 21:3 Page 10 of 17

heterogeneity among the included studies, mainly due to

differences between the archwire sequence in the fixed ap-

pliances and times of change for the aligners. In addition,

attempts were made to contact the authors by email to col-

lect missing data; however, only two of them responded,

and they sent all the data available. Additional information

still was not useful enough to justify a meta-analysis.

Discussion

In recent years, continuous search for esthetic alternatives

and comfortable orthodontic treatment approaches have

been reasons for significant increases in the number of

cases treated with clear aligners. Recent studies have shown

that patients specifically treated with Invisalign were satis-

fied with their esthetic results and showed an improvement

in their QoL, especially when related to their smile and dur-

ing chewing and eating functions analyzed after treatment

[13,27]. However, concerning the efficacy of treatment, re-

cent systematic reviews have suggested that this treatment

modality presents some difficulties on specific orthodontic

movements when compared with fixed appliances such as

in rotation and vertical movements [14], ideal occlusal con-

tacts, torque control, increasing transverse width and reten-

tion [16]. In addition, a study that evaluated the results of

treatments performed with Invisalign and conventional

brackets according to the American Board of Orthodontics’

objective classification system showed that treatment with

fixed appliances are relatively superior than the treatment

performed with Invisalign [28].

Despite the fact that fixed appliances have been the most

effective traditional method for orthodontic treatment for

many years and have shown good treatment efficiency, sev-

eral studies have reported the negative side effects of this

technique, especially plaque accumulation and difficulty of

oral hygiene [26,29]. Another important aspect commonly

observed is pain experience and discomfort during ortho-

dontic treatment [30]since91–95% of patients experience

some level of pain at different stages of treatment [8].

Pain is provoked by noxious stimuli and is a complex ex-

perience [30]. Therefore, it is important to understand the

pain pattern during orthodontic treatment because pain and

discomfort are two of the main reasons that affect the pa-

tient’s QoL during treatment [31]. In addition, fear of pain is

one of the main reasons for discouraging orthodontic treat-

ment [32] and previous studies have found that 8% [33]to

30% [34] of patients discontinue orthodontic treatment due

to pain experienced at the early stages of treatment.

Four studies [10,11,13,25] reported higher levels of

pain for the group treated with fixed appliances during the

first 24 h after beginning treatment, which corroborates

with other studies [6,35,36], which show that the highest

levels of pain are found 1 day after inserting initial arch-

wires. Furthermore, the literature also shows that the pain

is more intense during the first 3 days and is slowly

minimized or disappears on the seventh day. This is in

agreement with most of the included studies of this sys-

tematic review [2,10,11,20]. This pattern of pain occurs

due to initial orthodontic forces that cause discomfort due

to compression of the periodontal ligament, leading to is-

chemia, edema [37], and release of inflammatory media-

tors during the first 24–48 h [38]. These mediators such

as prostaglandins (e.g., PgE) and interleukins (e.g., IL-1β)

sensitize nociceptors of the periodontal ligament, increas-

ing discomfort. The levels of these mediators found in the

gingival cervical fluid peak 24 h after the onset of ortho-

dontic force and return to the reference values after 7 days

[39]. This explains the pattern of pain observed during the

first week after the application of orthodontic force.

Although the periods of higher and lower pain levels

were similar for the fixed and Invisalign treated groups, in

the present systematic review only one study [12]showed

higher levels of pain for the group treated with aligners.

They reported that this result may have been found due to

a greater mechanical force applied at the beginning of

Invisalign treatment; however, the sequence, time of use,

and period of exchange of the aligners were not described.

Understanding that pain can affect the QoL of the indi-

vidual, which can lead to worsening oral hygiene and have

a psychosocial impact [40], many patients use analgesics for

pain relief caused by orthodontic treatment. In the present

systematic review, five studies reported the use of analgesics

[2,10–12,25], and in all of them, the use of analgesics was

similar to the periods of higher and lower pain levels. The

perception of orthodontic pain is due to changes in blood

flow caused by the appliances, and the use of analgesic may

reduce the inflammatory process, consequently reducing

the pain levels [41], although the use of these pain relief

medications may mask the real pain reported by the pa-

tients leading to an uncertain result. Medication intake was

higher in the fixed appliance group than in the Invisalign

group as previously reported in the literature [8,35]. The

fact that patients with fixed appliances take more medica-

tions may underestimate the pain reported by them when

treated with this type of appliance.

However, pain is a subjective process and can be influ-

enced by several factors. Studies show that pain may be

related to the individual’s personality and that patients

who have some knowledge about orthodontic treatment

and have more positive attitudes presented lower levels

of pain during treatment [42,43]. Therefore, it is sug-

gested that the professionals inform the patients of any

discomfort that may occur during orthodontic treatment

and guide ways to alleviate it [42].

Knowing that the activation of the fixed appliance is

done once a month and the aligners changed every 15

days, it may be reasonable to think that patients treated

with aligners report lower pain levels at each activation,

but it is felt for a longer period of time. That said, it is

Cardoso et al. Progress in Orthodontics (2020) 21:3 Page 11 of 17

important to point out that few studies have evaluated

pain over a longer period of treatment. A randomized

clinical trial [2] performed this evaluation for 2 months

and observed the pain in the subsequent appointments

was lower in both groups. In the second month of main-

tenance, no statistical difference was observed.

The types of archwires should be taken in account since

they have differences in some mechanical properties such

as low elasticity module and coefficient of attrition, high

resilience, flexibility and elastic recovery, and biocompati-

bility that are important characteristics to stimulate the

adequate tissue response [44–46]. A laboratory study

demonstrates that nickel-titanium archwire with addition

of copper (CuNiTi) presented less favorable biologically

deactivation loads compared to the other thermoactivated

NiTi [47] which is consistent with a systematic review and

meta-analyses [48] that found that patients treated with

CuNiTi archwires presented greater levels of pain in the

Likert scale than those patients treated with NiTi.

However, lower levels of pain found in patients treated

with Invisalign may be related to the fact that removable

appliances produce less tension, pressure, sensitivity, and

pain than fixed appliances [49]. This reduced discomfort in

clear aligners may be associated with proinflammatory me-

diatorssuchasIL-1βbecause in the short term, these medi-

ators increase sensitization by triggering receptor-

associated kinases and ion channels, and in the long term,

they persuade the transcriptional upregulation of receptors,

leading to hyperalgesia [50]. So, it is reasonable to state that

removable appliances predisposed to painless responses

due to the intermittent forces when compared to the con-

tinuous forces of the fixed appliances [51]. Furthermore,

they can be removed by the patients themselves for pain re-

lief. In addition, it was hypothesized by one study [12]that

these results among non-randomized investigations should

be evaluated with caution since cases treated with Invisalign

usually have lower rates of irregularity index, and this dif-

ference may influence the patient’s perception of pain,

which is considered an important bias in the interpretation

of the results. In this systematic review, only two studies [2,

10] considered crowding level as inclusion criteria, and in

both of them, they range from mild to moderate. However,

the other five studies [11–13,20,25]didnotdescribeany

information, and none of the included studies reported any

differences in irregularity index between the evaluated

groups. Despite that, there are controversial results about

the correlation between the irregularity index and the per-

ception of pain. Some studies found that there is no correl-

ation [52–54], but a recent one found that crowding is a

risk factor, and with each increase in crowding, there is a

1.10 times increase in painful sensation [55].

Another relevant factor is the type of malocclusion in-

cluded in the studies. Some studies did not report inclu-

sion criteria adequately [11–13,20], and among those

who reported [2,10,25], all included patients with mild

or moderate malocclusion, Angle Class I malocclusion,

and crowding of up to 5 mm, which may bias the results,

since the more severe the malocclusion, the more it is

related to the psychosocial well-being of the patient in

pain-related scales, psychological discomfort, and social

problems [56].

Overall, the present systematic review showed lower pain

levels for the groups treated with Invisalign during the first

days of treatment. The studiespresentedahighmethodo-

logical quality according to the grading system, with the

RoB varying from moderate [12,20,25] to high in five stud-

ies [11,13], and only two [2,10]ofthestudiespresenteda

low RoB. Pain is one of many considerations, and predict-

ability and technical outcome are more important, mainly

considering that the difference does not seem to occur after

thefirstmonthsoftheorthodontictreatment.

Limitations

There is a high level of heterogeneity in the design of

the studies included in this systematic review. Among

these studies, we observed a great variation in relation to

the types of fixed appliance used, and five different types

were externally funded by companies. In addition, the

sequence of the archwires used and the set of the aligner

was poorly detailed. Both factors can strongly affect the

results found in this systematic review.

Selection of the participants was only randomized in

one study [2] that presented a high certainty of evidence.

In all other studies [10–12,20,25], that were classified

with low certainty of evidence, selection was done accord-

ingtotheorderofappearanceofpatientsseekingortho-

dontic treatment, and in some cases, the patient chose

which type of device they wanted to be treated with.

In addition, the use of analgesics was not reported in

all studies. This may be likely a significant confounding

factor since it is well established in the literature that the

use of this drug camouflages the actual levels of pain

produced during orthodontic treatment.

No other clear aligner appliances were studied in the

included studies. No conclusions/suggestions can there-

fore be made about other alternatives.

Conclusion

Orthodontic patients treated with Invisalign appear to re-

port lower levels of pain than those treated with fixed ap-

pliances during the first few days of treatment. However,

the type of malocclusions was not comprehensively de-

scribed which may lead to controversial results. Thereafter

(up to 3 months), differences were not noted. Malocclu-

sion complexity level among included studies was mild.

Based on the level of certainty, the results should be

evaluated with caution, and it is suggested that studies

with better methodological qualities be performed.

Cardoso et al. Progress in Orthodontics (2020) 21:3 Page 12 of 17

Appendix

Table 8 Database and Search Strategy

Database Search Strategy

Pubmed Search ((((((((((Orthodontic Appliances[MeSH Terms]) OR Orthodontic Appliances[Title/Abstract]) OR Appliance, Orthodontic[Title/

Abstract]) AND Appliances, Orthodontic[Title/Abstract]) OR Orthodontic Appliance[Title/Abstract])) OR

(((((((((((((((((((((((((((((Orthodontic Appliances, Fixed[MeSH Terms]) OR Orthodontic Appliances, Fixed[Title/Abstract]) OR Appliance,

Fixed Orthodontic[Title/Abstract]) OR Appliances, Fixed Orthodontic[Title/Abstract]) OR Fixed Orthodontic Appliance[Title/

Abstract]) OR Fixed Orthodontic Appliances[Title/Abstract]) OR Orthodontic Appliance, Fixed[Title/Abstract]) OR Fixed Functional

Appliances[Title/Abstract]) OR Appliance, Fixed Functional[Title/Abstract]) OR Appliances, Fixed Functional[Title/Abstract]) OR

Fixed Functional Appliance[Title/Abstract]) OR Functional Appliance, Fixed[Title/Abstract]) OR Functional Appliances, Fixed[Title/

Abstract]) OR Fixed Retainer[Title/Abstract]) OR Fixed Retainers[Title/Abstract]) OR Retainer, Fixed[Title/Abstract]) OR Retainers,

Fixed[Title/Abstract]) OR Bonded Retainer[Title/Abstract]) OR Bonded Retainers[Title/Abstract]) OR Retainer, Bonded[Title/Abstract])

OR Retainers, Bonded[Title/Abstract]) OR Fixed Appliances[Title/Abstract]) OR Appliance, Fixed[Title/Abstract]) OR Appliances,

Fixed[Title/Abstract]) OR Fixed Appliance[Title/Abstract]) OR Permanent Retainer[Title/Abstract]) OR Permanent Retainers[Title/

Abstract]) OR Retainer, Permanent[Title/Abstract]) OR Retainers, Permanent[Title/Abstract])) OR ((((((((((((((((((((((((((Orthodontic

Appliances, Removable[MeSH Terms]) OR Orthodontic Appliances, Removable[Title/Abstract]) OR Appliance, Removable

Orthodontic[Title/Abstract]) OR Appliances, Removable Orthodontic[Title/Abstract]) OR Orthodontic Appliance, Removable[Title/

Abstract]) OR Removable Orthodontic Appliance[Title/Abstract]) OR Removable Orthodontic Appliances[Title/Abstract]) OR Clear

Dental Braces[Title/Abstract]) OR Brace, Clear Dental[Title/Abstract]) OR Braces, Clear Dental[Title/Abstract]) OR Clear Dental

Brace[Title/Abstract]) OR Dental Brace, Clear[Title/Abstract]) OR Dental Braces, Clear[Title/Abstract]) OR Clear Aligner

Appliances[Title/Abstract]) OR Aligner Appliance, Clear[Title/Abstract]) OR Aligner Appliances, Clear[Title/Abstract]) OR Appliance,

Clear Aligner[Title/Abstract]) OR Appliances, Clear Aligner[Title/Abstract]) OR Clean Dental Braces[Title/Abstract]) OR Brace, Clean

Dental[Title/Abstract]) OR Braces, Clean Dental[Title/Abstract]) OR Clean Dental Brace[Title/Abstract]) OR Dental Brace, Clean[Title/

Abstract]) OR Dental Braces, Clean[Title/Abstract]) OR Invisalign[Title/Abstract]) OR Invisaligns[Title/Abstract])) OR (((Traditional

Brackets[Title/Abstract]) OR Edgewise appliance[Title/Abstract]) OR Passive self-ligating[Title/Abstract]))) AND (((((((((Pain

Perception[MeSH Terms]) OR Pain Perception[Title/Abstract]) OR Pain Perceptions[Title/Abstract]) OR Perception, Pain[Title/

Abstract]) OR Perceptions, Pain[Title/Abstract])) OR (((((((((((((((((((((((((((((((((((((((((((((((Pain Measurement[MeSH Terms]) OR Pain

Measurement[Title/Abstract]) OR Measurement, Pain[Title/Abstract]) OR Measurements, Pain[Title/Abstract]) OR Pain

Measurements[Title/Abstract]) OR Assessment, Pain[Title/Abstract]) OR Assessments, Pain[Title/Abstract]) OR Pain

Assessments[Title/Abstract]) OR Pain Assessment[Title/Abstract]) OR Analgesia Tests[Title/Abstract]) OR Analgesia Test[Title/

Abstract]) OR Test, Analgesia[Title/Abstract]) OR Tests, Analgesia[Title/Abstract]) OR Nociception Tests[Title/Abstract]) OR

Nociception Test[Title/Abstract]) OR Test, Nociception[Title/Abstract]) OR Tests, Nociception[Title/Abstract]) OR McGill Pain

Questionnaire[Title/Abstract]) OR Pain Questionnaire, McGill[Title/Abstract]) OR Questionnaire, McGill Pain[Title/Abstract]) OR

McGill Pain Scale[Title/Abstract]) OR Pain Scale, McGill[Title/Abstract]) OR Scale, McGill Pain[Title/Abstract]) OR Visual Analog Pain

Scale[Title/Abstract]) OR Visual Analogue Pain Scale[Title/Abstract]) OR Analogue Pain Scale[Title/Abstract]) OR Analogue Pain

Scales[Title/Abstract]) OR Pain Scale, Analogue[Title/Abstract]) OR Pain Scales, Analogue[Title/Abstract]) OR Scale, Analogue

Pain[Title/Abstract]) OR Scales, Analogue Pain[Title/Abstract]) OR Analog Pain Scale[Title/Abstract]) OR Analog Pain Scales[Title/

Abstract]) OR Pain Scale, Analog[Title/Abstract]) OR Pain Scales, Analog[Title/Abstract]) OR Scale, Analog Pain[Title/Abstract]) OR

Scales, Analog Pain[Title/Abstract]) OR Formalin Test[Title/Abstract]) OR Formalin Tests[Title/Abstract]) OR Test, Formalin[Title/

Abstract]) OR Tests, Formalin[Title/Abstract]) OR Tourniquet Pain Test[Title/Abstract]) OR Pain Test, Tourniquet[Title/Abstract]) OR

Pain Tests, Tourniquet[Title/Abstract]) OR Test, Tourniquet Pain[Title/Abstract]) OR Tests, Tourniquet Pain[Title/Abstract]) OR

Tourniquet Pain Tests[Title/Abstract])) OR (((((Patient Comfort[MeSH Terms]) OR Patient Comfort[Title/Abstract]) OR Comfort,

Patient[Title/Abstract]) OR Comfort Care[Title/Abstract]) OR Care, Comfort[Title/Abstract])) OR (((((Toothache[MeSH Terms]) OR

Toothache[Title/Abstract]) OR Toothaches[Title/Abstract]) OR Odontalgia[Title/Abstract]) OR Odontalgias[Title/Abstract])) Sort by:

Best Match

Search ((((((((((Orthodontic Appliances[MeSH Terms]) OR Orthodontic Appliances[Title/Abstract]) OR Appliance, Orthodontic[Title/